Some 50% of high-grade serious ovarian adenocarcinoma (HGS-OvCa) tumors may benefit from treatment with PARP inhibitors, and other commonly deregulated pathways in the disease could provide other opportunities for the development of new drugs, claim scientists for The Cancer Genome Atlas (TCGA) Research Network.

In what they claim is the most comprehensive and integrated analysis of cancer genes carried out for any cancer type to date, TCGA partners analyzed messenger RNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 HGS-OvCa tumors, and carried out whole-exon sequencing in 316 of these tumors. The results led to the identification of specific subtypes of the disease, and gene-expression signatures that predicted poor or good survival.

The data in addition suggested that 68 genes could be targeted by existing FDA-approved or experimental therapeutics. The overall findings are published in Nature in a paper titled “Integrated genomic analyses of ovarian carcinoma.”

Some 70% of ovarian cancer deaths are in patients with advanced-stage HGS-OvCa, the authors report, but standard treatment comprising aggressive surgery followed by platinum–taxane chemotherapy still leads to the recurrence of platinum-resistant cancer in about 25% of patients within six months, and the overall five-year survival probability is 31%. The evident lack of successful treatment strategies led TCGA researchers to carry out a comprehensive evaluation of genomic and epigenomic abnormalities on clinically annotated HGS-OvCa samples, to identify molecular abnormalities that influence disease pathophysiology, and potentially find new therapeutic targets.

Whole exome sequencing was carried out on DNA isolated from 316 HGS-OvCA samples and matched normal samples for each individual. Significantly, the tumor suppressor TP53 was mutated in 303 of 316 samples, and BRCA1 and BRCA2 had germline mutations in 9% and 8% of cases, respectively, and showed somatic mutations in a further 3% of cases. Six other genes were mutated in a statistically significant number of cases: RB1, NF1, FAT3, CSMD3, GABRA6 and CDK12. CDK12 is involved in RNA splicing regulation, has previously been implicated in lung and large intestine tumors, the authors note.

Copy-number analysis of the 489 HGS-OvCa genomes to identify recurrent focal somatic copy-number alterations (SCNAs) identified 63 regions of focal amplification, including 26 that encoded eight or fewer genes. The most common focal amplifications encoded CCNE1, MYC, and MECOM, each of which was highly amplified in more than 20% of tumors, while 22 amplified genes representing potential therapeutic targets were amplified in at least 10% of cases. Conversely, copy-number analyses also identified 50 focal deletions. Interestingly, regions of homozygous deletions present in at least 2% of tumors harbor the tumor suppressor genes PTEN, RB1, and NF1.

mRNA and miRNA expression and DNA methylation analyses of the 489 samples suggested that HGS-OvA exists as at least four expression subtypes, which the researchers termed immunoreactive, differentiated, proliferative, and mesenchymal, on the basis of the gene content in the clusters. These four subtypes did not seem to correlate with patient survival, however. Significantly, the team identified a 193-gene transcriptional signature that predicted overall survival. 108 genes were correlated with poor survival and 85 genes correlated with good survival. The predictive power of these expression signatures were validated on an independent set of 255 samples, and on three independent expression datasets. Patients with a poor survival expression signature survived an average 23% shorter than other patients.

Integrated data from the 316 fully analyzed cases were then evaluated to try and identify putative biological contributions to HGS-OvCa. Analysis of the frequency with which known cancer-associated pathways harbored one or more mutations, copy-number changes or changes in gene expression showed that the RB1 and PI3K/RAS pathways were deregulated in 67% and 45% of cases, respectively, and the NOTCH signaling pathway was altered in 22% of HGS-OvCa samples, providing potentially therapeutic targets.

Looking more closely at BRCA1 and BRCA2 specifically, the researchers found that 20% of the HGS-OvCa samples had germline or somatic mutations in BRCA1/2, while 11% had lost BRCA1 expression through DNA hypermethylation. Interestingly, cases with BRCA1/2 mutations were associated with better survival than those with normal BRCA1/2 genes. An exception to this was in cases with epigenetically silenced BRCA1, which were associated with a similar survival to that of wild-type HGS-OvCa tumors. “This suggest that BRCA1 is inactivated by mutually exclusive genomic and epigenomic mechanisms and that patient survival depends on the mechanism of inactivation,” the authors note.

Further analyses suggested that 50% of the HGS-OvCa demonstrated defects in other homologous recombination genes, “providing a rationale for clinical trials of PARP inhibitors targeting tumors with these homologous-recombination-related aberrations,” they state. “Overall, the mutational spectrum was surprisingly simple,” the authors conclude. “Mutations in TP53 predominated, occurring in at least 96% of HGS-OvCa samples, and BRCA1 and BRCA2 were mutated in 22% of tumors, owing to a combination of germline and somatic mutations. Seven other significantly mutated genes were identified, but only in 2–6% of HGS-OvCa samples ... these discoveries set the stage for approaches to the treatment of HGS-OvCa in which aberrant genes or networks are detected and targeted with therapies selected to be effective against these specific aberrations.”

The Cancer Genome Atlas Network is jointly funded and managed by NIH’s National Cancer Institute and the National Human Genome Research Institute.

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